This invention is for novel glutamate receptor antagonists which are new compounds of the 5,6,7,8-substituted quinoxaline 2,3-dione type. The fused ring system is substituted at the a- or b-position by amino acid derivatives. The compounds are active as excitatory amino acid receptor antagonists acting at glutamate receptors, including either or both N-methyl-D-aspartate (NMDA) receptors and non-NMDA receptors such as the .alpha.-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor and the kainate receptor. The invention also relates to the use of those quinoxaline-2,3-diones as neuroprotective agents for treating conditions such as cerebral ischemia or cerebral infarction resulting from a range of phenomena, such as thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma, as well as to treat chronic neurodegenerative disorders such as Alzheimer's Disease, Parkinsonism and Huntington's Disease, and as anticonvulsants. The compounds of the present invention may also be useful in the treatment of schizophrenia, epilepsy, anxiety, pain and drug addiction. Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA) glutamate and aspartate at the N-methyl-D-aspartate (NMDA) receptor, the .alpha.-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, and the kainate receptor. AMPA/kainate receptors may be referred to jointly as non-NMDA receptors. This excitotoxic action is considered responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma, as well as lathyrism, Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease.
Several classes of quinoxalinedione derivatives have been disclosed as glutamate (EAA) receptor antagonists. For example, among excitatory amino acid receptor antagonists recognized for usefulness in the treatment of disorders are those that block AMPA receptors (Bigge C. F. and Malone T. C., Curr. Opin. Ther. Pat., 1993:951; Rogawski M. A., TiPS, 1993;14:325). AMPA receptor antagonists have prevented neuronal injury in several models of global cerebral ischemia (Li H. and Buchan A. M., J. Cerebr. Blood Flow Metab., 1993;13:933; Nellg ard B. and Wieloch T., J. Cerebr. Blood Flow Metab., 1992;12:2) and focal cerebral ischemia (Bullock R., Graham D. I., Swanson S., McCulloch J., J. Cerebr, Blood Flow Metab., 1994;14:466; Xue D., Huang Z.-G., Barnes K., Lesiuk H. J., Smith K. E., Buchan A. M., J. Cerebr. Blood Flow Metab., 1994;14:251). AMPA antagonists have also shown efficacy in models for analgesia (Xu X.-J., Hao J.-X, Seiger A., Wiesenfeld-Hallin Z., J. Pharmacol. Exp. Ther., 1993;267:140), and epilepsy (Namba T., Morimoto K., Sato K., Yamada N., Kuroda S., Brain Res., 1994;638:36; Brown S. E., McCulloch J., Brain Res., 1994;641:10; Yamaguchi S. I., Donevan S. D., Rogawski M. A., Epilepsy Res., 1993;15:179; Smith S. E., Durmuller N., Meldrum B. S., Eur, J, Pharmacol., 1991;201:179). AMPA receptor antagonists have also demonstrated promise in chronic neurodegenerative disorders such as Parkinsonism (Klockgether T., Turski L., Honor e T., Zhang Z., Gash D. M., Kurlan R., Greenamyre J. T., Ann. Neurol., 1993;34(4):585-593).
Excitatory amino acid receptor antagonists that block NMDA receptors are also recognized for usefulness in the treatment of disorders. NMDA receptors are intimately involved in the phenomenon of excitotoxicity, which may be a critical determinant of outcome of several neurological disorders. Disorders known to be responsive to blockade of the NMDA receptor include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, neuropathic pain, and anxiety, and may be a significant causal factor in chronic neurodegenerative disorders such as Parkinson's disease (Klockgether T., Turski L., Ann. Neurol., 1993;34:585-593), human immunodeficiency virus (HIV) related neuronal injury, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (Francis P. T., Sims N. R., Procter A. W., Bowen D. M., J. Neurochem., 1993;60(5):1589-1604), and Huntington's disease. (See Lipton S., TINS, 1993;16(12):527-532; Lipton S. A., Rosenberg P. A., New Eng. J. Med., 1994;330(9):613-622; and Bigge C. F., Biochem. Pharmacol., 1993;45:1547-1561 and references cited therein.) NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control withdrawal symptoms from addictive drugs (Eur. Pat. Appl. 488,959A).
Copending U.S. Ser. No. 08/124,770 discloses glutamate receptor antagonist quinoxalinedione derivatives represented by the formula: ##STR1## wherein A is a 5 to 7 atom containing ring having a nitrogen which may be substituted by hydrogen, alkyl, or CH.sub.2 CH.sub.2 OH. This application does not disclose or suggest compounds having the instant amino as substituents, or the requisite methodology to prepare the same.
Copending application U.S. Ser. No. 08/404,400 teaches glutamate receptor antagonists which are quinoxalinediones of formula ##STR2## or a pharmaceutically acceptable salt thereof wherein
R.sup.1 is hydrogen, an alkyl, or an alkylaryl;
X and Y are independently hydrogen, halogen, nitro, cyano, trifluoromethyl, COOH, CONR.sub.4 R.sup.5, SO.sub.2 CF.sub.3, SO.sub.2 R.sup.4, SONR.sup.4 R.sup.5, alkyl, alkenyl, (CH.sub.2).sub.z CONR.sup.4 R.sup.5, (CH.sub.2).sub.z COOR.sup.4, or NHCOR.sup.4, wherein R.sup.4 and R.sup.5 are independently hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl, or alkylaryl, and z is an integer from 0 to 4;
R.sup.2 is alkylCOOR.sup.3, alkylamine, alkylquanidine, aryl, alkylaryl, COalkyl, COalkylaryl, CONR.sup.3 alkyl, CONR.sup.3 aryl, CONR.sup.3 alkylaryl, CSNR.sup.3 alkyl, CSNR.sup.3 alkylaryl or a common amino acid moiety joined by an amide bond, wherein R.sup.3 is hydrogen, alkyl, or alkylaryl; and
m and n are independently 0, 1, or 2 provided that m+n is &gt;1.
This application does not disclose or suggest the compounds of the instant invention having amines as substituents at the a- or b-positions nor the methodology to prepare them.
JP06228112-A discloses glutamate receptor antagonists which are quinoxaline-2,3(1H,4H)-dione derivatives of formula ##STR3## wherein R.sup.1 is H, NO.sub.2, or CF.sub.3 ;
Ring A is a nitrogen-containing saturated heterocyclic group which may contain sulfur or oxygen; PA1 R.sup.2 is H, OH, lower alkoxy, COOH, lower alkoxy carbonyl, NH.sub.2, or lower alkoxy, carbonyl-amino. This reference does not teach or suggest the instant compounds which must be attached to the quinoxaline dione fused ring system by an alkylene. PA1 R.sup.1 represents hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl; PA1 G represents --CONR.sup.2 -- or --NR.sup.2 CO--, wherein R.sup.2 represents hydrogen or alkyl; PA1 J represents an acidic group or a group which is convertible thereto in vivo; PA1 E represents a basic group or a group which is convertible thereto in vivo; PA1 Y represents a single bond, alkylene, alkenylene, substituted alkylene, or Y.sup.1 --Q--Y.sup.2, wherein Y.sup.1 represents a single bond or alkylene, Y.sup.2 represents alkylene, and Q represents a heteroatom selected from oxygen or sulfur; and PA1 Z represents alkylene. PA1 X is O or NOR.sup.2, wherein R.sup.2 is hydrogen, alkyl, or benzyl; PA1 Y is N--R.sup.4, wherein R.sup.4 is hydrogen, OH, or alkyl; PA1 n is 0 or 1; PA1 R.sup.6 is phenyl, naphthyl, thienyl, pyridyl, all of which may be substituted one or more times with substituents selected from the group consisting of halogen; PA1 CF.sub.3, NO.sub.2, amino, alkyl, alkoxy, and phenyl; and PA1 A is a ring of 5 to 7 atoms fused with the benzo ring at the positions marked a and b. PA1 n is an integer of from 1 to 4; PA1 R.sub.1 is hydrogen, alkyl, aralkyl, carboxyalkyl, phosphoroalkyl, or phosphonoalkyl; PA1 R.sub.2 is hydrogen, hydroxy, or amino; PA1 R.sub.3 and R.sub.4 are each independently hydrogen, alkyl, cycloalkyl, alkenyl, halogen, haloalkyl, nitro, cyano, SO.sub.2 CF.sub.3, C(O)R.sub.6 wherein R.sub.6 is hydroxy, alkoxy, ##STR9## alkyl, haloalkyl, aryl, aralkyl, CH.sub.2 SO.sub.2 R.sub.6, (CH.sub.2).sub.m CO.sub.2 R.sub.9 wherein R.sub.9 is hydrogen, alkyl, aralkyl, or cycloalkyl, (CH.sub.2).sub.m CONR.sub.7 R.sub.8, (CH.sub.2).sub.m SO.sub.2 NR.sub.7 R.sub.8, or NHCOR.sub.6 wherein m is an integer of from 0 to 4 and R.sub.7 and R.sub.8 are each independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, or aralkyl; R.sub.5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, aryl, heteroaralkyl, aralkyl, heteroaryl, nitro, cyano, trifluoromethylsulfonyl, C(O)R.sub.6, (CH.sub.2).sub.m CO.sub.2 R.sub.9, (CH.sub.2).sub.m CONR.sub.7 R.sub.8, SONR.sub.7 R.sub.8, or NHCOR.sub.6 wherein m is as defined above and R.sub.7 and R.sub.8 are each independently hydrogen, alkyl, cycloalkyl, or aralkyl; and R.sub.5 may be at the b-position and R--(CH.sub.2).sub.n -- at the a-position on the ring. PA1 R is ##STR10## wherein R.sub.11 is hydrogen, alkyl, or aralkyl, and R.sub.12 is an amino acid of formula ##STR11## wherein p is an integer of from 1 to 5 and R.sub.17 and R.sub.18 are each independently on any carbon in --(C)p-- and wherein R.sub.16 is hydroxy, alkoxy, NR.sub.19 R.sub.20 wherein R.sub.19 and R.sub.20 are each independently hydrogen, alkyl, cycloalkyl, or aralkyl, and R.sub.17 and R.sub.18 are independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaralkyl, carboxyalkyl, aminoalkyl, thioalkyl, or hydroxyalkyl; PA1 R.sub.1 is hydrogen, alkyl, aralkyl, carboxyalkyl, phosphoroalkyl, or phosphonoalkyl; PA1 R.sub.2 is hydrogen, hydroxy, or amino; PA1 R.sub.3 and R.sub.4 are each independently hydrogen, alkyl, cycloalkyl, alkenyl, halogen, haloalkyl, nitro, cyano, SO.sub.2 CF.sub.3, C(O)R.sub.6, CH.sub.2 SO.sub.2 R.sub.6, (CH.sub.2).sub.n CO.sub.2 R.sub.9, (CH.sub.2).sub.n CONR.sub.7 R.sub.8, (CH.sub.2).sub.n SO.sub.2 NR.sub.7 R.sub.8, or NHCOR.sub.6 wherein n is an integer of from 0 to 4 and R.sub.6 as defined earlier, R.sub.7, and R.sub.8 are each independently selected from hydrogen, alkyl, cycloalkyl, or aralkyl, and PA1 R.sub.5 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, aryl, aralkyl, heteroaryl, nitro, cyano, SO.sub.2 CF.sub.3, C(O)R.sub.6 wherein R.sub.6 is hydroxy, alkoxy, ##STR12## alkyl, haloalkyl, aryl, or aralkyl, (CH.sub.2).sub.m CO.sub.2 R.sub.9, (CH.sub.2).sub.m CONR.sub.7 R.sub.8, SONR.sub.9 R.sub.10, or NHCOR.sub.6 wherein m is as defined above and R.sub.7 and R.sub.8 are each independently hydrogen, alkyl, cycloalkyl, or aralkyl; and R.sub.5 may also be at the b-position and R--(CH.sub.2).sub.n -- at the a-position on the ring. PA1 wherein R is ##STR13## wherein R.sub.11 is hydrogen or methyl, wherein R.sub.12 is ##STR14## wherein R.sub.16 is hydroxy, alkoxy, or amide, and R.sub.17 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaralkyl, carboxyalkyl, aminoalkyl, thioalkyl, or hydroxyalkyl; PA1 R.sub.1 is hydrogen; PA1 R.sub.2 is hydrogen; PA1 R.sub.3 and R.sub.4 are each independently hydrogen, halogen, or nitro; PA1 R.sub.5 is hydrogen, alkyl, or alkenyl.
WO 93/08188 covers a tricyclic quinoxalinedione of formula ##STR4## as useful or selective antagonists of glutamate receptors.
European Patent Application 0627434 covers tricyclic quinoxalinedione of Formula I below which are selective antagonists of glycine binding site of the NMDA receptor ##STR5## wherein X represents hydrogen, alkyl, halogen, cyano, trifluoromethyl, or nitro;
WO 94/26747 discloses compounds of Formula I below as useful in the treatment of cerebrovascular disorder ##STR6## wherein R.sup.1 is hydrogen, alkyl or benzyl;
The compounds of the instant invention differ from the art in that they provide noncoplanar compounds with greater solubility and, therefore, better ability to penetrate the blood-brain barrier. These are important attributes in pharmaceuticals.
An object of this invention is to provide novel quinoxalinediones with amines at the a- or b-position which function as antagonists.